The objective of this project is the development of new chemotherapeutic agents for the control of human dental plaque and periodontal diseases. This objective will be accomplished by the design, synthesis, and selection of new agents derived from structural classes of currently known agents which have demonstrated some potential efficacy in clinical trials. In this project attention is focused upon those agents which may act by inhibition of microbial growth. Agents are favored which are very rapid acting or which exhibit properties resulting in their prolonged retention in the oral cavity. A newly discovered subclass of antimicrobial agents, the acylsalicylanilides, will be further developed and refined for this application. Several members of this class exhibit in vitro bactericidal effects upon Actinomycetes at concentrations 10 to 100 times lower than those required by tribromsalan or chlorhexidine. Both of the latter agents have been reported to reduce gingivitis in clinical studies. Acylsalicylanilides have been found which exert a complete bactericidal effect upon wire-formed bacterial coats of A. viscosus and Streptococcus mutans at 5- to 10-fold lower concentrations than those of chlorhexidine with a single two-minute treatment. Several of these new agents also appear superior to chlorhexidine in a new in vitro tooth slab assay which tests substantivity and growth inhibiting effects against Actinomycetes. Additional new agents in this and related classes will be prepared in repetitive cycles of syntheses and evaluations to develop advantages regarding: optimal in vitro antiplaque activity, enhanced spectra of antibacterial effects, low potential for systemic or chronic side-effects, and improved physical properties for the intended modes of administration. By employing in vitro antiplaque assays of several types, candidate agents are selected for further evaluations of toxicity and efficacy in a primate animal model for inhibition of plaque and gingivitis.